Epidemiologic studies suggest that the natural history of renal complications consists of a sequence of stages, the first being marked by the appearance of microalbuminuria. The next stage begins when microalbuminuria worsens to overt proteinuria, at which point progressive renal destruction leads to renal failure or premature atherosclerosis. The major factors implicated in the etiology of renal complications include genetic predisposition to hypertension, a variant of the type IV Collagen gene, and environmental exposures such as poor glycemic control and high protein intake. The goal of this research is to test the hypothesis that these several factors are differentially involved at each stage. A two-phase design will be used. The first will be a large case-control study of 1000 individuals with Type I diabetes, 500 with microalbuminuria and 500 with no evidence of nephropathy, to determine risk factors for the development of incipient nephropathy. Genetic predisposition to hypertension will be assessed by the Vmax of Li-Na countertransport in red cells. The genotypes of Type IV collagen will be assessed using certain RFLPs for the collagen IV alpha 1 gene. Usual dietary protein intake will be assessed using a semi-quantitative food frequency questionnaire, and five year history of glycemic control will be assessed using HbA1 and index of hyperglycemia. The second phase of the proposed study will be a follow-up of the group of cases to determine which factors influence progression to overt proteinuria. The results of this research will enable us to identify which factors are influential in the earliest stages of diabetic nephropathy. This will not only increase understanding of the pathophysiology of renal complications in diabetes, but it will also enable us to devise programs aimed at the prevention of the onset of early nephropathy or its progression to established nephropathy, a state which inevitably leads to renal failure or premature atherosclerosis.